GPCR Selectivity Beyond the Receptor — Live April 9th with Bryan Roth
- Yamina Berchiche
- Apr 7
- 4 min read
Bryan Roth joins the Dr. GPCR community live this week to examine what happens when GPCR selectivity is encoded not at the receptor, but at the receptor–transducer interface. T
This is one of 12+ live Masterclasses planned for 2026 — all included in Premium, each one a direct scientific exchange with a leading scientist, with full replay access afterward.
Also this week: Terry Hébert previews his April 16 session on iPSC-derived translational models, and a new podcast episode with Joseph Kim on GPCR structural biology and drug discovery at opioid and galanin receptors.
GPCR Selectivity: Allosteric Modulators as Intracellular Molecular Glues
Standard models attribute signaling specificity to ligand-stabilized receptor conformations — a framework that does not fully account for selectivity that can also emerge from receptor–transducer complex stabilization. SBI-553 at NTSR1 and PCO371 at PTH1R illustrate how intracellular modulators engage cytoplasmic interfaces directly, stabilizing specific receptor–transducer assemblies across GPCR families A, B, and T.
This session with Bryan Roth will cover how intracellular modulation controls G protein and arrestin coupling — and whether the molecular glue framing offers a productive framework
for targeting gain- and loss-of-function diseases.
In 48h: April 9, 2026, 10 AM EST
This live session with recording available as well as all masterclasses are now included in Premium. Not a member yet? Explore the Dr. GPCR University
iPSC-Derived Systems for GPCR Signaling and Translation
HEK293 systems are powerful tools for pharmacological screening, but they have a structural limitation when signaling outcomes depend on cell type, signaling complex assembly, and disease biology.
Terry Hébert's upcoming session examines how patient-derived induced pluripotent stem cells (iPSCs), organoid systems, and biosensor-based assays extend GPCR pharmacology into disease-relevant environments, with dilated cardiomyopathy as a concrete model system.
Next week: April 16, 2026, 10 AM EST.
This live session with recording available as well as all masterclasses are now included in Premium. Not a member yet? Explore the Dr. GPCR University
Terry's Corner AMA — How Important Is It to Know Where Your Molecule Binds?
Whether a molecule binds at the orthosteric or allosteric site determines its pharmacological behavior entirely. An orthosteric compound hijacks the target and imposes its own efficacy.
An allosteric compound works in concert with endogenous signaling, producing a different pattern entirely. In this live AMA, Terry Kenakin will the methods that differentiate these binding modes and why this distinction carries practical consequences for drug discovery programs at any stage.
Thursday, April 16, 1:00 PM ET — note the adjusted time.
Send us your questions ahead of time at Terry@DrGPCR.org
Dr. Joseph Kim: Structural Biology and Drug Discovery at GPCRs
Cryo-EM has transformed how we visualize receptor–ligand interactions — and with it, how we think about drug discovery at GPCRs. In this episode, Joseph Kim, a postdoctoral scholar in Ashish Manglik's lab at UCSF, discusses structural studies of opioid receptors, the challenge of peptide-binding GPCRs, and why understudied receptors like the galanin family may be worth revisiting with today's tools.
One small molecule studied in the Manglik lab interacts with both the μ- and κ-opioid receptors, acting differently at each — a concrete illustration of how receptor-specific pharmacology complicates drug discovery and why structural insights matter.
Quick Links
GPCR Antibody Validation in Real Systems → Request GeneTex samples
Biased Signaling Microcircuits in Drug Discovery → Read DiscoverX article
A2A Fluorescent Competitive Binding with NanoBRET® → Explore assay approach
This Week's Scientific Highlight
Binder2030: a quantitative membrane proteome binding dataset enabling AI-driven drug discovery
Membrane proteins represent more than half of therapeutic targets but remain underrepresented in quantitative ligand-binding datasets. Binder2030 addresses this gap — a curated affinity selection-mass spectrometry dataset comprising 3,384 small-molecule ligands across approximately 400 transmembrane proteins, including GPCRs, SLC transporters, and ion channels.
Standardized Kd measurements enable comparative analysis of affinity distributions and chemical space across target classes, with downstream integration demonstrated in a structure-based modeling workflow comparing Boltz-2 predicted potencies with experimental affinities for a GlyT-1 ligand set.
From the Masterclass Library
This week's featured course from the Masterclass Library: Unconventional GPCR Ligands with Terry Kenakin. Classic hormones and small molecules no longer capture the full complexity of GPCR targeting.
This course examines prodrugs, biologics, irreversible inhibitors, and molecular glues — and how these unconventional ligand classes address long-standing challenges in selectivity, efficacy, and clinical translation.
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Premium Members are reading 15 new publications this week, including a quantitative membrane proteome binding dataset enabling AI-driven drug discovery. Plus 6 industry updates and 1 new Masterclass recording now available — Purinergic GPCR Ligand Design with Kenneth Jacobson and Matteo Pavan.
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